Chimeric flavivirus vaccines

Abstract

A chimeric live, infectious, attenuated virus containing a yellow fever virus, in which the nucleotide sequence for a prM-E protein is either deleted, truncated, or mutated, so that functional prM-E protein is not expressed, and integrated into the genome of the yellow fever virus, a nucleotide sequence encoding a prM-E protein of a second, different flavivirus, so that the prM-E protein of the second flavivirus is expressed.

1 . A chimeric live, infectious, attenuated virus, comprising:
 a yellow fever virus in which the nucleotide sequence encoding a prM-E protein is either deleted, truncated, or mutated so that functional yellow fever virus prM-E protein is not expressed, and   integrated into the genome of said yellow fever virus, a nucleotide sequence encoding a prM-E protein of a second, different flavivirus, so that said prM-E protein of said second flavivirus is expressed.   
     
     
         2 . The chimeric virus of  claim 1 , wherein said second flavivirus is a Japanese Encephalitis (JE) virus, a Dengue virus, a Murray Valley Encephalitis virus, a St. Louis Encephalitis virus, a West Nile virus, a Tick-borne Encephalitis virus (i.e., a Central European Encephalitis virus or a Russian Spring-Summer Encephalitis virus), a Hepatitis C virus, a Kunjin virus, a Powassan virus, a Kyasanur Forest Disease virus, or an Omsk Hemorrhagic Fever virus. 
     
     
         3 . The chimeric virus of  claim 2 , wherein said second flavivirus is a Dengue virus selected from the group consisting of Dengue types 1, 2, 3, and 4. 
     
     
         4 . The chimeric virus of  claim 3 , wherein said nucleotide sequences derived from said Dengue virus are derived from two or more different Dengue strains. 
     
     
         5 . (canceled) 
     
     
         6 . The chimeric virus of  claim 1 , wherein the nucleotide sequence encoding the prM-E protein of said second, different flavivirus replaces the nucleotide sequence encoding the prM-E protein of said yellow fever virus;
 said nucleotide sequence encoding said prM-E protein of said second, different flavivirus comprises a mutation that prevents prM cleavage to produce M protein;   the prM signal of said chimeric virus is that of yellow fever virus; and/or   the NS2B-NS3 protease recognition site and the signal sequences and cleavage sites at the C/prM and E/NS1 junctions are maintained in construction of said chimeric flavivirus.   
     
     
         7 - 9 . (canceled) 
     
     
         10 . A method of preventing or treating flavivirus infection in a patient, said method comprising administering to said patient a chimeric, live, infectious, attenuated virus comprising:
 a yellow fever virus in which the nucleotide sequence encoding a prM-E protein is either deleted, truncated, or mutated so that functional yellow fever virus prM-E protein is not expressed, and   integrated into the genome of said yellow fever virus, a nucleotide sequence encoding a prM-E protein of a second, different flavivirus, so that said prM-E protein of said second flavivirus is expressed.   
     
     
         11 . The method of  claim 10 , wherein said second flavivirus is a Japanese Encephalitis (JE) virus, a Dengue virus, a Murray Valley Encephalitis virus, a St. Louis Encephalitis virus, a West Nile virus, a Tick-borne Encephalitis virus (i.e., a Central European Encephalitis virus or a Russian Spring-Summer Encephalitis virus), a Hepatitis C virus, a Kunjin virus, a Powassan virus, a Kyasanur Forest Disease virus, or an Omsk Hemorrhagic Fever virus. 
     
     
         12 . The method of  claim 11  wherein said second flavivirus is a Dengue virus selected from the group consisting of Dengue types 1, 2, 3, and 4. 
     
     
         13 . The method of  claim 12 , wherein said nucleotide sequences derived from said Dengue virus are derived from two or more different Dengue strains. 
     
     
         14 . (canceled) 
     
     
         15 . The method of  claim 10 , wherein the nucleotide sequence encoding the prM-E protein of said second, different flavivirus replaces the nucleotide sequence encoding the prM-E protein of said yellow fever virus;
 said nucleotide sequence encoding said prM-E protein of said second, different flavivirus comprises a mutation that prevents prM cleavage to produce M protein;   the prM signal of said chimeric virus is that of yellow fever virus; and/or   the NS2B-NS3 protease recognition site and the signal sequences and cleavage sites at the C/prM and E/NS1 junctions are maintained in construction of said chimeric flavivirus.   
     
     
         16 - 18 . (canceled) 
     
     
         19 . A nucleic acid molecule encoding a chimeric live, infectious, attenuated virus comprising:
 a yellow fever virus in which the nucleotide sequence encoding a prM-E protein is either deleted, truncated, or mutated so that functional yellow fever virus prM-E protein is not expressed, and   integrated into the genome of said yellow fever virus, a nucleotide sequence encoding a prM-E protein of a second, different flavivirus, so that said prM-E protein of said second flavivirus is expressed.   
     
     
         20 . The nucleic acid molecule of  claim 19 , wherein said second flavivirus is a Japanese Encephalitis (JE) virus, a Dengue virus, a Murray Valley Encephalitis virus, a St. Louis Encephalitis virus, a West Nile virus, a Tick-borne Encephalitis virus (i.e., a Central European Encephalitis virus or a Russian Spring-Summer Encephalitis virus), a Hepatitis C virus, a Kunjin virus, a Powassan virus, a Kyasanur Forest Disease virus, or an Omsk Hemorrhagic Fever virus. 
     
     
         21 . The nucleic acid molecule of  claim 20 , wherein said second flavivirus is a Dengue virus selected from the group consisting of Dengue types 1, 2, 3, and 4. 
     
     
         22 . The nucleic acid molecule of  claim 21 , wherein said nucleotide sequences derived from said Dengue virus are derived from two or more different Dengue strains. 
     
     
         23 . (canceled) 
     
     
         24 . The nucleic acid molecule of  claim 19 , wherein the nucleotide sequence encoding the prM-E protein of said second, different flavivirus replaces the nucleotide sequence encoding the prM-E protein of said yellow fever virus;
 said nucleotide sequence encoding said prM-E protein of said second, different flavivirus comprises a mutation that prevents prM cleavage to produce M protein;   the prM signal of said chimeric virus is that of yellow fever virus; and/or   the NS2B-NS3 protease recognition site and the signal sequences and cleavage sites at the C/prM and E/NS1 junctions are maintained in construction of said chimeric flavivirus.   
     
     
         25 - 27 . (canceled) 
     
     
         28 . A method of producing a gene product in a cell in a patient, said method comprising introducing into said cell a yellow fever virus vector comprising a gene encoding said gene product. 
     
     
         29 . The method of  claim 28 , wherein said cell is a cell of the lymphoid system or the reticuloendothelial system, or a precursor thereof. 
     
     
         30 . The method of  claim 28 , wherein said patient has cancer. 
     
     
         31 . The method of  claim 30 , wherein said cancer is leukemia. 
     
     
         32 . The method of  claim 30 , wherein said gene product is a tumor antigen or a cytokine.